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Editorials, Perspectives, and Recognition Awards

Medawar Prize Acceptance Speech

Barker, Clyde

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doi: 10.1097/TP.0b013e3181fdda2e
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Finding that my name would be added to the list of Medawar Prize Awardees was a wonderful but humbling experience. I am grateful to the selection committee members, Nick Tilney, Kathryn Wood, David Sutherland, Oscar Salvatierra, and Carl Groth (also a Medawar Prize winner).

I also need to thank several other Medawar Prize laureates who introduced me to the field. In 1964 (2 years before this Society was formed) and shortly before I finished my residency, I visited several university centers to explore possible specialty career pathways. At the University of Colorado, Thomas Starzl invited me to scrub with him on a kidney transplant. This was an inspirational experience that sold me on pursuing a career in transplantation. Even more importantly during that visit to Denver, I found out that more than two third of Starzl's kidney transplant recipients were long-term successes. At Pennsylvania, I had been told that success was too unlikely to justify embarking on transplantation at a conservative institution like ours. In fact, Starzl's results were unique (1, 2). At that time, more of his kidney recipients were alive with functioning grafts than those of the rest of the world's combined programs (3, 4). My enthusiastic description of the Colorado results persuaded the authorities at Pennsylvania that it might be time to attempt transplantation. To my surprise, I was chosen to start the program. Fortunately, my first kidney transplant worked. If it had failed, I doubt that I would have had the chance to deliver this speech. Remarkably, that kidney is still working after 44 years.

My interest as an experimentalist began with a 6-week sabbatical from Pennsylvania that I spent in 1965 at Massachusetts General Hospital with two other Medawar Prize winners: Paul Russell and Tony Monaco. They and their marvelous technician Mary Wood introduced me to the rudiments of transplantation biology and the technique of skin grafting.

On returning to Pennsylvania, I was presented with the most important opportunity of my professional life to study with Rupert Billingham, first as a postdoctoral fellow and then for 6 years as a junior faculty member of his Department of Genetics (Fig. 1A). He suggested that I join him in the attempt to construct an artificial immunologically privileged transplant site based on ablation of draining lymphatic vessels. Although the absence of lymphatic drainage from several classic privileged sites, such as the hamster's cheek pouch and the brain, had been proposed as a likely explanation for the protection they afforded implanted allografts, evidence for this until then was indirect.

FIGURE 1.
FIGURE 1.:
(A) Rupert Billingham in laboratory. (B) Alymphatic, skin flap, an artificial immunologically privileged site we constructed in guinea pigs (5).

The privileged site we designed was formed by surgically separating from the flank of guinea pigs a small disk of skin with its underlying muscle (5) (Fig. 1B). Carefully preserved in the dissection was a single vascular bundle, which served as an “umbilical cord” to nourish the otherwise completely detached skin flap. Dye injected into such flaps outlined a rich lymphatic network within their confines, but no lymphatic vessels were found leaving the flaps along the umbilical cord. Shallow beds were cut in the flap to accommodate skin allografts. These allografts avoided rejection and survived as long as the flaps remained viable (sometimes more than 100 days). Rejection of control orthotopic skin allografts took place in only 8 to 10 days. Subsequent skin grafting tests demonstrated that intraflap allografts did not sensitize their hosts. However, if recipients had been specifically presensitized by orthotopic skin allografts, the intraflap allografts were promptly rejected. Furthermore, active or adoptive immunization of hosts bearing established, healthy intraflap allografts brought about their prompt demise, leaving no doubt that the efferent arc of the immunologic reflex was intact. This simple surgical model demonstrated that to initiate the process of skin allograft rejection, the alloantigenic message must reach regional lymph nodes. Thirty years later, Fadi Lakkis using mice with congenitally absent lymph nodes extended this principle of “immunologic ignorance” (6).

For the remainder of the 15 min allotted for my acceptance speech, I confined myself to reminiscences of my participation in several favorite early Congresses of this Society. These had been high points in my life, and I was pleased to let these short presentations serve as a sampling of my experimental career. At the first Congress of the Transplantation Society in 1967, Billingham sent me to represent his department. For me and my wife, Dode, the combination of this week in Paris and participation in my first international meeting was a thrilling and totally addicting experience (Fig. 2A). I presented the guinea pig skin flap studies I have just described (7).

FIGURE 2.
FIGURE 2.:
(A) Dode and I attended the first Congress of the Transplantation Society in Paris. I presented the guinea pig skin flap study (7). (B) The pencil sketch was made by Medawar during my talk. His drawing suggested modification of our model to increase the dose of antigen by parabiosing the isolated flap to a “donor” animal.

An associated indelible memory was a brief conversation I had with Sir Peter Medawar just as I finished speaking. Medawar happened to be seated close behind me in the conference hall. He leaned over and handed me a pencil drawing that he had made during my talk (Fig. 2B). He suggested by the drawing that if we modified our model to increase the dose of antigen delivered to the flap by parabiosing it to an entire donor animal, we might find that lymphatic drainage was not crucial. We never tried his experiment, but I have kept the drawing as a treasured souvenir. At the second Congress in New York, I presented a joint project with Billingham on the hamster cheek pouch, another immunologically privileged site that lacked lymphatic drainage (8, 9).

In 1971, I began to experiment with pancreatic islet transplantation with Craig Reckard, a surgical resident in my laboratory. Our thought was that a small volume of isolated islets, unlike a whole organ, might be amenable to transplantation to a privileged site once again linked to the research focus of my early work with Billingham. At the same time, unbeknownst to us, two other groups were working independently on islet transplantation: one in St. Louis and the other in Minneapolis.

The fourth Congress of the Transplantation Society took place in San Francisco in September 1972. There, Reckard gave the first report of our success with islet transplantation in reversing diabetes in rats (Fig. 3) (10, 11). Earlier that year, the St. Louis workers, Ballinger and Lacy, had shown a similar although less complete impact of islet transplantation on diabetes (12). The Minnesota results were published still earlier (13) but are now seldom cited possibly because of the untimely death of the group leader, Arnold Lazarow.

FIGURE 3.
FIGURE 3.:
At the fourth Congress in San Francisco, as illustrated by this chart of plasma glucose, Reckard and I showed for the first time the complete and permanent reversal of chemically induced diabetes by transplantation of isolated pancreatic islets (10).

At the 1974 Congress in Jerusalem, Mory Ziegler presented our further studies to systematically dissect and overcome the immunologic barriers to long-term islet allograft acceptance (14) (Fig. 4).

FIGURE 4.
FIGURE 4.:
At the fifth Congress in Jerusalem, Ziegler showed the influence of histocompatibility and immunosuppression on the outcome of islet transplantation (14).

After detailing the response to islet allografts in animals whose diabetes was chemically induced, we investigated whether the procedure could succeed in spontaneous diabetics or whether the disease itself would destroy transplanted islets. Initially, with Leo Frangipane, a surgical resident, I transplanted islets to mouse models of type II diabetes (15). Not surprisingly, despite successful engraftment of the transplanted islets, these obese insulin-resistant animals remained hyperglycemic. We then turned our attention to type I diabetes. At that time, little was known about the cause of type I diabetes. Ali Naji, who was then a graduate student in my laboratory, and I set out to determine the possible role of autoimmunity, which at the time was controversial. We explored the outcome of islet transplantation in the then only available rodent model of spontaneous onset insulin-dependent diabetes, the BB rat (16).

Naji presented these experiments at the 8th Congress of the Society in Boston (17). The disease of these animals in many ways resembles human type I diabetes. They are at first normoglycemic but in early adulthood they become hyperglycemic. We were intrigued by the histologic picture of their islets seen at the onset of diabetes. The mononuclear infiltrate suggested an immunologically based lesion (Fig. 5). Because these rats were outbred, we could not avoid rejection by performing islet isografts. Therefore, to exclude rejection, we induced immunologic tolerance in prospective BB rat recipients by neonatal infusion of bone marrow from a prospective donor strain (Fig. 6A). Thus, we could assess the possible impact of autoimmunity on transplanted islets without a confounding alloimmune response. These experiments yielded several interesting findings. When our subjects spontaneously become diabetic, we transplanted them with islets from the strain to which we had induced tolerance. The transplant site was the liver through portal vein inoculation. Hyperglycemia was promptly reversed but diabetes recurred within 2 weeks, as the islets were destroyed (18) (Fig. 6B). However, donor strain skin allografts were accepted permanently confirming the persistence of tolerance to the donor strain. The histologic appearance of the failed transplanted islets had the trademark mononuclear infiltrate of an immunologically based lesion (Fig. 6C). It was similar to that we had found in the native islets in the pancreas at the time of their failure. These studies were the first to demonstrate that transplanted islets were a target of autoimmunity, and some of the first evidence that type I diabetes was an autoimmune disease. Subsequently, David Sutherland discovered that recurrent autoimmunity could also destroy the islets of human segmental pancreas grafts transplanted from identical twin donors (19). There was another important and quite unexpected finding of our BB rat studies. Of the diabetes-prone rats that as neonates had received the tolerizing inoculum of allogeneic bone marrow from normal rats, many never became diabetic (20). We found that the disease prevention in these animals was due to the generation of hematopoietic chimerism that countered an immunodeficient state we discovered and characterized in BB rats. This finding represented the first immunotherapy for autoimmune diabetes (21, 22).

FIGURE 5.
FIGURE 5.:
At the eighth Congress in Boston, Ali Naji presented studies of islet transplantation in BB rats that develop diabetes spontaneously. Illustrated is the mononuclear cell infiltration of an islet in the pancreas of a newly diabetic rat (5).
FIGURE 6.
FIGURE 6.:
(A) Neonatal induction of tolerance induces permanent acceptance of donor strain skin grafts. (B) Donor strain intrahepatic islet transplants initially reverse diabetes but are destroyed in 1 to 2 weeks, causing recurrence of hyperglycemia. Histologic examination of the liver revealed mononuclear cell infiltrate of transplanted islets (18).

Over the next decade, we devoted considerable attention to preventing islet rejection by means other than immunosuppression and neonatal tolerance. Pretransplant culture of islets was shown by Steve Bartlett and Will Silvers to prevent rejection. Surprisingly, this method was more effective for major histocompatibility complex disparate than major histocompatibility complex compatible donors (23–25).

Twenty- five years after the first Congress of the Transplantation Society, we returned to Paris for the 14th Congress. There, Andy Posselt, a graduate student working with Ali Naji, Jim Markmann, and Mike Choti presented our work on a new transplant site, the thymus (Fig. 7) (26). They first discovered that the thymus was a previously unrecognized immunologically privileged transplant site. After a single dose of antilymphocyte serum to deplete already mature peripheral T cells, allogeneic islets grafted to the thymus survived indefinitely (Fig. 8A and B). Even more significant was the striking impact the implanted islets had on central immune tolerance (27). The intrathymic islets rendered the host tolerant to the donor, allowing survival of subsequently transplanted extrathymic donor strain islet allografts (Fig. 8C). Jim Markmann reported that the T-cell repertoire developing in the presence of the intrathymic allograft was educated by deletion of donor-specific reactive T cells (28, 29). Jon Odorico and Luis Campos demonstrated that the cells used for the intrathymic inoculums could be bone marrow cells, T cells, or spleen cells instead of islets and that tolerance to heart and liver grafts was induced (30–33).

FIGURE 7.
FIGURE 7.:
Presentations at the 25th Congress dealt with exploration of the thymus as a transplant site (26).
FIGURE 8.
FIGURE 8.:
(A) Mature T cells are depleted with a single dose of antilymphocyte serum. (B) Allogeneic islets transplanted to the thymus are permanently accepted. (C) Subsequently, transplanted extrathymic islets are also accepted permanently without the need for immunosuppression (27).

Andy Posselt then demonstrated that even in BB rats with autoimmune diabetes, intrathymic islets experienced prolonged survival (34). Thus, recurrent autoimmunity could be prevented by the exposure of T cells during their ontogeny to islet autoantigens. A finding with even greater potential was that this approach could provide a simple means to prevent the onset of autoimmune diabetes. When a small clearly subtherapeutic number of islets were transplanted to the thymus of newborn diabetes-prone rats, this exposure to the islet graft's autoantigens prevented animals from ever developing diabetes (35, 36).

At the Kyoto Congress in 1994, interest generated by our intrathymic experiments resulted in multiple papers by other groups exploring this approach. The Pennsylvania contribution by my colleagues Ken Brayman and Mark Levy indicated the effectiveness in a canine model (37). Intrathymic tolerance has not yet been explored in humans, perhaps in part because of the atrophy that takes place in the adult human thymus.

Unfortunately, progress in human islet transplantation has also lagged far behind experimental work in animals. Until the last decade, the outcome of the limited number of human islet transplants performed was discouraging. Most totally failed to reverse diabetes or did so only briefly. Ricordi's (38) improved islet isolation process may have been largely responsible for somewhat better success in the late 1990s. Then in 2000, Shapiro et al. (39) from Edmonton, Canada, achieved reversal of diabetes in seven consecutive recipients, probably because of substantially increasing the number of islets transplanted by using for each recipient a series of transplants—an approach not previously used. At Pennsylvania, Jim Markmann and Ali Naji followed the “Edmonton Protocol” with similar early success (40). However, over the next 4 to 5 years, diabetes recurred in most islet recipients at Pennsylvania, Edmonton, and elsewhere. The reason for these late failures of initially successful transplants remains unknown. However, within the last 2 years, several programs including Ali Naji's at Pennsylvania are obtaining superior early transplant results possibly based on improved islet isolation and immunosuppressive protocols. Other reports at the Vancouver Congress suggest that these new trials may be lastingly successful. Even if not, I believe studies of islet transplantation such as those reviewed here have provided valuable insight into the immunopathogenesis of diabetes, which may ultimately lead to its cure or prevention.

The Kyoto Congress had an additional and very special meaning for Dode and me. My mentor Rupert Billingham was chosen to receive the Medawar Prize. Because of advanced Parkinson's disease, he was unable to attend. At the awards ceremony, it was my privilege to join Leslie Brent (also a Medawar Prize winner) in introductory remarks, acknowledging Billingham's prize (41) (Fig. 9A). Later, Dode and I delivered the plaque to him at his home in Martha's Vineyard (Fig. 9B).

FIGURE 9.
FIGURE 9.:
Because of illness, Rupert Billingham was unable to travel to Japan for the 15th Congress to receive his Medawar Prize. (A) I made introductory remarks for him and joined Leslie Brent in accepting his award. (B) My wife and I later presented the award to him at his home in Martha's Vineyard (41).

In my remarks about Billingham at the Congress, I told a story I had heard from him many times before (42). At a cocktail party, a colleague asked Medawar to help distinguish fraternal from identical twin pairs in cattle. Medawar proposed the obvious solution of exchanging skin grafts between twins and with reluctance agreed to perform the grafts along with his graduate student Billingham. Neither of them had much enthusiasm for the experiment because they considered the outcome to be totally predictable. In addition, Medawar disliked working with cows. These photographs of Medawar taken by Billingham suggest his casual distain for the project (Fig. 10). When they finished, he said, “Thank God, we've left those cows behind.”

FIGURE 10.
FIGURE 10.:
Peter Medawar skin grafting a twin cow and relaxing afterward. Because he did not like working with cows, he enlisted the help of his graduate student, Rupert Billingham, who also took the photographs. Also shown in the picture is Medawar's technician, Jean Morpeth, who later married Billingham. She is also seen in Figure 9 (42).

But these skin grafts turned out to be the making of their careers. The results were quite different than they expected. Almost all skin grafts were accepted, whether exchanged between fraternal or identical twins (43). The interpretation that initially confounded them made sense only when their attention was called to a 5-year-old article by Ray Owen (another Medawar Prize laureate). Owen had shown that cattle twins are lastingly chimeric because unlike most other species, cattle twins freely exchange blood in utero as their placentas are fused (44). The genius of the soon to follow Billingham, Brent, and Medawar mouse project on tolerance was to reproduce in mice the experiment that nature had performed in cows (45).

In finishing, I should pay tribute to the previous Medawar laureates and thank those especially relevant to my career: Sir Peter Morris, a special friend for many favors; my early mentors, Paul Russell and Tony Monaco; tennis friends, Roy Calne and Joe Murray; other friends, Dick Simmons, Leslie Brent, Paul Teresaki, Carl Groth, and Max Dubernard; and finally two particularly important mentors and role models who gave me my start in transplantation, Rupert Billingham and Thomas Starzl. Their continued counsel, support, and friendship have been so important that I could never be able to thank them properly.

Finally, it is important to remember the eponymic source of this prize, Sir Peter Medawar, the Society's first President and the founder of transplantation immunology (Fig. 11). Although himself a laboratory researcher, Medawar always looked ahead to the application of transplantation to human disease. Thus, unlike some basic scientists who advocated fully solving problems of rejection in the laboratory before clinical trials, he never attempted to hold back the pioneering of human kidney transplantation that was going on in Denver, Boston, Richmond, and Paris.

FIGURE 11.
FIGURE 11.:
Sir Peter Medawar.

For the benefit of those who never met Medawar, I showed during my speech a video clip that I hoped would capture for them a trace of the charm that was part of his magic. In the clip, Medawar said, “I think I can speak for all surgeons and all people like myself working in the laboratory when I say that our ultimate ambition is that transplantation methods should be received into the perfectly ordinary repertoire of surgical practice.”

I do not think transplantation is yet perfectly ordinary, but it is getting closer and is in fact the best treatment for several fatal or disabling diseases. Medawar would no doubt be pleased with its progress, as illustrated by the scientific program of this Society's 23rd Congress in Vancouver.

I knew Medawar chiefly through Billingham and by reading some of his essays and books. Many of them are on the philosophy of science (46, 47). I will mention two practical spin-offs of the philosophy that Billingham said he learned from Medawar and which Billingham passed along to his students (42) (Fig. 12).

FIGURE 12.
FIGURE 12.:
Billingham and Medawar in 1980 examining skin grafts on an armadillo. According to Billingham, a photography enthusiast, Medawar was a bit camera shy. This may be the only photograph of the two of them together.
  1. In an experiment, pay attention to or even hope for an unexpected finding. Explaining such a finding is much more likely to be worthwhile than merely confirming a pet hypothesis. For Medawar and Billingham, an example of this was their unexpected discovery that skin grafts exchanged between fraternal cattle twins are not rejected. For me and my colleagues, examples of this were the autoimmune destruction of transplanted islets and intrathymic tolerance.
  2. Devote as much time and effort to the written or oral presentation of your work as to the conduct of the experiments. This may require altering the source of the hypotheses, the sequence of the experiments, or reasons for doing them. Maintain the sanctity of the data but do whatever else it takes to make your presentation conclude with the impact of a well-contrived detective story. Medawar and Billingham were masters of this art form. Among more recent practitioners of the painstakingly crafted scientific essay are Nick Tilney, Leslie Brent, and Tom Starzl.

Whether I have induced my students to follow Medawar's advice is uncertain, but I do know that the credit for this wonderful prize really belongs to those on this long but incomplete list of my students and fellows (Fig. 13). They did the work and had many of the ideas. I like to think of them as third- and fourth-generation progeny of Sir Peter Medawar.

FIGURE 13.
FIGURE 13.:
University of Pennsylvania students and fellows, 1971–2010.

REFERENCES

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